Final clinical results and first translational correlates of a phase 2 trial of adaptively dosed nivolumab and ipilimumab based on early radiographic assessment in advanced melanoma (ADAPT-IT).
Authors: James William Smithy, Hannah L Kalvin, Vladislav Raber, Colleen Anne Maher, Jenna Kleman, Debra AG McIntyre, Alexander Noor Shoushtari, Allison Betof Warner, Margaret K. Callahan, Parisa Momtaz, Omar Eton, Suresh Nair, Jedd D. Wolchok, Paul B. Chapman, Katherine Panageas, Michael A. Postow
Journal: Journal of Clinical Oncology (2023)

9517 Background: Initial results from ADAPT-IT (NCT03122522) demonstrated that adaptive dosing of nivolumab (nivo) and ipilimumab (ipi) based on early radiographic assessment was associated with comparable response rates and toxicity compared to historical data for conventional nivo + ipi. Here, we report the final clinical analysis, including median progression-free survival (PFS), and present the first correlative analyses of blood-based biomarkers of response. Methods: ADAPT-IT was a multicenter, phase 2 clinical trial with a planned sample size of 60 patients with unresectable melanoma. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients with early favorable antitumor effect (FATE; defined as the absence of new lesions and ≤ 4% index lesion tumor growth), discontinued ipi and continued nivo alone. Patients without FATE at week 6 received third and fourth doses of nivo + ipi followed by nivo alone. The primary endpoint was investigator-assessed overall response rate (ORR; defined as the percent of patients with complete or partial responses by RECIST v1.1) at week 12. A Simon two-stage design was employed where a 43% 12-week ORR was considered not promising, a 60% 12-week ORR was considered promising, and the probabilities of type I and type II error were each set at 0.10. Pre- and on-treatment peripheral blood samples were assayed for 1) ten cytokines using a multiplex immunoassay (Meso Scale Diagnostics) and 2) circulating tumor DNA (ctDNA) using the MSK-ACCESS sequencing platform. The Wilcoxon rank sum test and Cox regression modeling were used to evaluate associations between biomarker levels with radiographic response and PFS, respectively. Results: 60 patients were enrolled. Week 12 and best ORR were 48% (95% CI, 35-61%) and 58% (95% CI, 45-71%), respectively. Median follow-up was 34 months (interquartile range: 21-36) in survivors, median PFS was 21 months (95% CI: 11-not reached) and the median overall survival was not reached. There were no new Grade 3-5 treatment-related adverse events since the initial report. Higher baseline IL-6 was observed in non-responders compared to responders (p = 0.03; n = 26) and was associated with shorter PFS (HR for progression or death 1.24; 95% CI: 1.01-1.52; p = 0.04). Among 20 patients with detectable ctDNA at baseline (of 25 patients with available samples), an increase in mean adjusted variant allele fraction from baseline to week 6 was associated with shorter PFS (HR 1.14; 95% CI: 1.02-1.27; p = 0.02). Conclusions: In this updated analysis, now with long-term follow-up, the efficacy of adaptively dosed nivo + ipi resembles that of historical data for standard dose nivo + ipi. Baseline IL-6 and on-treatment changes in ctDNA warrant further prospective study as biomarkers of response to ipi + nivo. Clinical trial information: NCT03122522 .